To better understand why bone is lost in disorders like periodontal disease, it is necessary to understand the control mechanisms which regulate the formation of new bone. Osteoinduction is the term given to the technique where bone is induced to form when demineralized allogeneic bone or proteins from bone are implanted in nonosseous sites. We know very little about the factors in bone which initiate or sustain this osteoinductive stimulus. Several potent growth factors have now been identified in bone, many of which have already been shown to have activity against bone and isolated bone cells. The objective of this proposal is to establish whether these newly recognized factors play a role in the osteoinductive process. We hope this will provide insights into the role these factors play in bone formation. The approach we intend to use is to combine these factors with purified osteoinductive factor in a well characterized subcutaneous implant model for osteoinduction. Using three different modes of delivery, we will determine whether increased local concentrations of the factors are able to alter the pattern of bone formation we see. Particular attention will be paid to changes in the cells which populate the implant, the pattern of mineralization associated with bone formation, and the amount of bone which is induced to form. Quantitative evaluation of these and other parameters will allow an accurate judgement of any role these factors may play in the osteoinductive process. We also intend to correlate in vivo osteioinduction with in vitro responses in established bone cell lines. From these studies we hope to develop the basis for in vitro assays which are truly predictive of in vivo osteoinductive activity.